Improved delivery of fenoterol plus ipratropium bromide using Respimat1 compared with a conventional metered dose inhaler

Transcription

1 Eur Respir J 2001; 17: Printed in UK all rights reserved Copyright #ERS Journals Ltd 2001 European Respiratory Journal ISSN Improved delivery of fenoterol plus ipratropium bromide using Respimat1 compared with a conventional metered dose inhaler J. Goldberg*, E. Freund #, B. Beckers #, R. Hinzmann # Improved delivery of fenoterol plus ipratropium bromide using Respimat1 compared with a conventional metered dose inhaler. J. Goldberg, E. Freund, B. Beckers, R. Hinzmann. #ERS Journals Ltd ABSTRACT: Asthma can be effectively treated by the use of bronchodilator therapies administered by inhalation. The objective of this study was to describe the dose-response relationship of combined doses of fenoterol hydrobromide (F) and ipratropium bromide (I) (F/I) delivered via Respimat1, a soft mist inhaler, and to establish the Respimat1 dose which is as efficacious and as safe as the standard marketed dose of F/I (100/40 mg) which is delivered via a conventional metered dose inhaler (MDI). In a double-blind (within device) cross-over study with a balanced incomplete block design, 62 patients with stable bronchial asthma (mean forced expiratory volume in one second (FEV1) 63% predicted) were randomized at five study centres to receive five out of eight possible treatments: placebo, F/I 12.5/5, 25/10, 50/20, 100/40 or 200/80 mg delivered via Respimat1; F/I 50/20 or 100/40 mg delivered via MDI. Pulmonary function results were based on the per-protocol dataset, comprising 47 patients. All F/I doses produced greater increases in FEV1 than placebo. A log-linear dose-response was obtained for the average increase in FEV1 up to 6 h (AUC 0 6 h ) and peak FEV1 across the dose range administered by Respimat1. Statistically, therapeutic equivalence was not demonstrated between any F/I dose administered by Respimat1 compared with the MDI. However 12.5/5 and 25/10 mg F/I administered via Respimat1 were closest (slightly superior) to the F/I dose of 100/40 mg delivered via MDI. Pharmacokinetic data from 34 patients indicated a two-fold greater systemic availability of both drugs following inhalation by Respimat1 compared to MDI. In general, the active treatments were well tolerated and safe with regard to vital signs, electrocardiography, laboratory parameters and adverse events. In conclusion, combined administration of fenoterol hydrobromide and ipratropium bromide via Respimat1, is as effective and as safe as higher doses given via a metered dose inhaler. Eur Respir J 2001; 17: *Ambulantes Gesundheitszentrum GmbH, Schwedt, Germany and # Boehringer Ingelheim KG, Ingelheim am Rhein, Germany. Correspondence: J. Goldberg, Ambulantes Gesundheitszentrum GmbH, Passower Chaussee (Strasse 1), D Schwedt/Oder, Germany Fax: Keywords: Asthma bronchodilator agents fenoterol ipratropium Respimat1 soft mist inhaler Received: July Accepted after revision September National and international guidelines for the management of asthma recommend the inhalation of shortacting beta 2 -agonists, when required by the patient, as an initial bronchodilation therapy for acute severe asthma [1 6]. In addition, this can be supplemented with anticholinergics where there is inadequate control of asthma [7]. The sympathomimetic agent, fenoterol hydrobromide (F), has a high potency and selectivity for beta 2 - adrenoreceptors and elicits bronchodilation by relaxing bronchial smooth muscle. Ipratropium bromide (I) has a different mechanism of action, acting as an anticholinergic agent at muscarinic receptors in the respiratory tract to relieve bronchoconstriction. The two compounds also differ in pharmacodynamics, with F having a rapid onset of action, causing prompt, shortacting bronchodilation. In contrast, I has a slower onset but prolonged duration of action. This complementary mechanism between F and I has led to their use in fixed dose combinations for several years [8 11]. There are currently a range of inhaler devices available for delivering antiasthma therapies [12]. Metered dose inhalers (MDIs) are the most common, because of their safety, efficacy and ease of use. However, these devices use chlorofluorocarbon (CFC) propellants which are being withdrawn because of environmental concerns [13]. There are alternatives for CFC-driven MDIs under development, some of which are already available. These include MDIs containing hydrofluoroalkane propellants and dry powder inhalers (DPIs) [14, 15], with each device having advantages and disadvantages based on lung deposition characteristics, reliability, consistency and ease of use. In addition, Respimat1 (Boehringer Ingelheim KG, Ingelheim, Germany) has been developed: a reusable, mechanically-driven, propellant free, multi-dose, soft mist inhaler (SMI). Respimat1 releases the drug solution as a soft mist over a period of 1.2 s, at a particle velocity (y10 m. s -1 ) five times slower than from conventional MDIs [16]. In addition, a high proportion of the drug dose is in the fine particle fraction (particles with diameter v5.8 mm). Scintigraphic studies have demonstrated that the smaller particle size and lower velocity of the dose from Respimat1 improves lung deposition

2 226 J. GOLDBERG ET AL. compared to conventional MDIs [17 23]. Furthermore, clinically relevant bronchodilation has been observed in 2-way crossover pilot studies with a prototype SMI delivering either F or I, in asthmatics or chronic obstructive pulmonary disease patients [24, 25]. The present study was designed to assess the efficacy and safety of the Respimat1 in delivering combined doses of F and I (F/I), compared with a conventional MDI, in patients with stable asthma. Patients Materials and methods Patients eligible for the study were those aged yrs, with stable perennial bronchial asthma as defined by the American Thoracic Society [26]. At the initial screening visit, each patient provided written informed consent and underwent a complete medical examination to fulfil inclusion and exclusion criteria. Included patients had stable asthma with no hospital admission for an exacerbation and with no major change in medication for 6 weeks prior to the trial. All included patients had an initial forced expiratory volume in one second (FEV1) of 40 80% of the predicted normal value according to standard criteria [27, 28]. In addition, all patients exhibited reversible airway obstruction as shown by an increase in FEV1 of 15% within 60 min after inhaling two puffs of 50/ 20 mg F/I via MDI without a spacer, following withdrawal of other bronchodilatory drugs. Furthermore, baseline FEV1 for each patient, on each test day, had to be within 20% and 0.3 L of that obtained on the first test day. Eligible subjects were nonsmokers or exsmokers who had given up smoking for 1 yrand with a history of no more than ten pack years. Subjects were excluded if they had a respiratory tract infection, severe exacerbation of asthma within 6 weeks prior to the trial, or were intolerant to the study drugs of excipients. Patients were also ineligible if they were pregnant or lactating, receiving oral corticosteroids within 6 weeks prior to the study, or receiving betablockers. Appropriate withdrawal times were used for other pulmonary medications (antihistamines 48 h, inhaled short-acting beta 2 -sympathomimetics 8 h, inhaled long-acting beta 2 -sympathomimetics 48 h, inhaled anticholinergics 12 h, slow release xanthines 72 h). Use of inhaled cromolyn sodium/nedocromil and stable use of inhaled corticosteroids was permitted until 1 h before pre-dose evaluation of pulmonary function. Sixty-two eligible patients were randomised. The data of eight patients from one test centre were excluded from efficacy and safety analyses because of major protocol violations. The remaining 54 patients were included in the safety analysis. Fifty patients were included in the intent-to-treat efficacy data set, since one patient withdrew after the first test day and three patients were excluded due to insufficient data. Following the early discontinuation of a further patient, and exclusion of two others with incomplete data, the per-protocol analysis was finally based on 47 patients without major protocol violations (table 1). This trial was carried out in accordance with the principles of the declaration of Helsinki and approved by the Ethics Committee of the Federal Chamber of Physicians of Rhineland-Palatinate (Landesärztekammer von Rheinland-Pfalz). Study design In a randomised, five-period cross-over (balanced incomplete block) design at five study centres, included patients received five out of these eight possible treatments: placebo; F/I doses of 12.5/5, 25/10, 50/20, 100/40 or 200/80 mg delivered via Respimat1; or F/I doses of 50/20 or 100/40 mg delivered using a conventional MDI. On each test day, patients inhaled either one puff from Respimat1 or two puffs delivered via MDI: either two puffs of 50/20 mg or one puff of 50/ 20 mg F/I plus one puff placebo MDI (all devices from Boehringer-Ingelheim KG). Treatment was open label between devices and double-blind within each device. Patients9 pulmonary function (FEV1 and forced vital capacity (FVC)), adverse events and vital signs were evaluated until 6 h after inhalation as described below. Test days were 2 days apart and medication was inhaled at the same time on each test day 0.5 h, between 07:00 h and 10:00 h. Methods Pulmonary function (FEV1, FVC) was measured by spirometry at baseline, then at 5, 15, 30, 60 and 90 min and at 2, 3, 4, 5 and 6 h after administration of the test drug on all test days. The primary endpoint was the average FEV1 in litres. This was determined as area under the curve for FEV1 change from test day baseline up to 6 h divided by 6 h (AUC 0 6 h ). Secondary endpoints used to assess patient bronchodilatory responses were the peak change in FEV1, time to onset and duration of the therapeutic response, and time to peak therapeutic response. A therapeutic response was defined as an FEV1 measurement exceeding the predose value by 15% at any time throughout the 6-hour observation period. Time to onset was defined as the linear interpolation of the time of the first therapeutic response and the time of the observation just prior to the first therapeutic response (even if it was the predose value). The systemic pharmacokinetics of F and I were also evaluated as a secondary endpoint, and determined by measuring plasma levels and urinary excretion of both drugs following delivery in 34 patients from two study centres. Plasma concentrations of F or I were measured in blood sampled pre-dose and at 3, 10, 59 and 119 min after inhalation. Urinary excretion of both drugs was evaluated by collecting urine samples pre-dose and in the time intervals and h after inhalation of the test drug. The concentrations of F and I were measured using a radioimmunoassay and radioreceptor assay, respectively. The urinary excretion data were pooled from 0 6 h. The limits of quantification of these assays were 20 pg. ml -1 for F in plasma and urine, and 50 and 200 pg. ml -1 for I in plasma and urine,

3 FENOTEROL/IPRATROPIUM DELIVERY BY RESPIMAT1 227 Table 1. Patient demographics and baseline characteristics Parameter All randomized patients Per-protocol patients Value Range Value Range Males/females 32/30 22/25 Age yrs* Median duration of asthma yrs Never smoked/exsmokers n 41/21 31/16 Baseline FEV1 L* Baseline FVC L* Baseline FEV1/FVC %* FEV1 % predicted* Post-dose FEV1 L* FEV1 increase %* *: Data presented as mean SD. FEV1: forced expiratory volume in one second; FVC: forced vital capacity. respectively. The radioreceptor assay was not sensitive enough to measure the concentration of I in plasma up to the nominal dose of 40 mg with both devices. Consequently, the pharmacokinetic evaluation of I is confined to the urinary data, pooled from 0 6 h. Physical examinations and laboratory safety screens were carried out upon admission, and on the last test day. Cardiac frequency and blood pressure (BP) were monitored and recorded before testing on all test days. A 12-lead electrocardiography (ECG) recording was made at screening and on the last test day ( 5 h after inhalation). All adverse events were recorded by the investigator with particular attention given to cough, wheezing and paradoxical bronchoconstriction. Paradoxical bronchoconstriction was defined as a 15% fall in FEV1 below baseline at or before 5, 15 and 30 min following inhalation of the test drug. Clinically significant changes in vital signs were defined as follows: 1) systolic BP decrease: below 100 mmhg with a decrease of more than 20 mmhg below baseline; 2) systolic BP increase: above 150 mmhg with an increase of 25 mmhg above baseline; 3) diastolic BP decrease: below 60 mmhg with a decrease of more than 10 mmhg below baseline; 4) diastolic BP increase: above 90 mmhg with an increase of more than 10 mmhg above baseline; 5) cardiac frequency decrease: below 50 beats. min -1 with a decrease of more than 10 beats. min -1 below baseline; and 6) cardiac freqency increase: above 100 beats. min -1 with an increase of more than 20 beats. min -1 above baseline. Statistical analysis The primary hypothesis of interest was to demonstrate a dose-response relationship over the dose range studied, based on AUC 0 6 h. The expected difference in AUC 0 6 h between the lowest and highest dose administered via Respimat1 was 0.15 L. Allowing for a balanced incomplete 5-period design with 8 treatments, a sample size of 40 patients was required to detect this treatment difference at a two-sided 5% level of significance with 90% power. The primary efficacy analysis was performed on the per-protocol data set including patients with at least predose and one postdose FEV1 on 2 test days, excluding patients with major protocol violations. The intent-to-treat data set, including all patients who had satisfactory pre- and post-dose data on 2 test days was used to confirm the results of the primary analysis on the per-protocol data set. Least square means were obtained using analysis of variance (ANOVA) suitable for cross-over studies. The factors included in the ANOVA were centre, patient within centre, period and treatment. ANOVA was used to compare the highest and lowest doses of Respimat1. Therapeutic equivalence between MDI and Respimat1 was addressed by calculating the 90% confidence intervals for the adjusted mean difference between each dose of Respimat1 and MDI, accompanied by a test of whether the difference between the pairs of treatments are likely to be as much as 0.15 L. More than one dose from Respimat1 was expected to be therapeutically equivalent to the MDI and with only 40 patients, the estimates of the means were expected to be imprecise. Therefore, a log dose-response curve was fitted visually and used to select the point on the Respimat1 log dose-response curve which falls closest to the standard dose of MDI. Secondary analyses were performed on the per-protocol data set to compare each Respimat1 dose and placebo. All analyses were also repeated for the secondary endpoint peak FEV1 increase. The least square means for FEV1 and FVC at each time point were obtained by performing a separate ANOVA at each time point using the model described above. The least square means were plotted against time for each treatment. The numbers of patients with adverse events were tabulated by treatment. Adjusted mean changes in blood pressure and pulse rate from pre-dose were analysed using ANOVA at each time point as described for spirometry. The statistical analyses were performed using the Statistical Analysis System (SAS) (version 6.08, SAS Institute Inc., Cary, NC, USA). Efficacy Results All F/I treatments produced significantly greater increases in FEV1 than placebo (p~0.0001). The adiusted mean time-response curves show the bronchodilator efficacy of all drug treatments across the dose range studied (fig. 1). Adjusted AUC 0 6 h, following

4 228 J. GOLDBERG ET AL. FEV1 L Time min F/I doses of 12.5/5, 25/10, 50/20, 100/40 and 200/80 mg administered via Respimat1 were 0.60, 0.73, 0.79, 0.90 and 1.03 L, respectively, compared with 0.14 L after placebo Respimat1 administration. The adjusted AUC 0 6 h showed a log-linear dose-response relationship across the dose range administered by Respimat1 (fig. 2). A similar relationship was not detected for the two doses of F/I administered by MDI; AUC 0 6 h was slightly higher for the lower dose, at 0.67 L compared with 0.64 L for the higher dose. AcomparisonofAUC 0 6 h between the lowest and highest doses of F/I (12.5/5 and 200/80 mg) demonstrated that bronchodilation was significantly greater for the higher dose (p~0.0001: treatment difference 0.42 L; 95% confidence interval L). Comparisons between devices for AUC 0 6 h failed to demonstrate therapeutic equivalence between any of the F/I doses delivered by Respimat1 and the conventional MDI dose (100/40 mg). However, AUC 0 6 h values for F/I doses of 12.5/5 and 25/10 mg Fig. 1. Change in mean forced expiratory volume in one second (DFEV1) from pre-dose after inhalation of fenoterol and ipratropium administered by Respimat1 (RMT) or metered dose inhaler (MDI) (per-protocol dataset). Y: RMT placebo;.: RMT 25/10 mg; &: RMT 100/40 mg; +: MDI 50/20 mg; e: RMT 12.5/5 mg; #: RMT 50/20 mg; %: RMT 200/80 mg; ': MDI 100/40 mg. AUC 0-6h L /5 25/10 50/20 100/40 200/80 Dose µg Fig. 2. Dose-response curve of mean change in forced expiratory volume in one second (AUC 0 6 h ) from pre-dose. %: Respimat1; &: MDI (metered dose inhaler). Respimat F/I dose µg 200/80 100/40 50/20 25/ /5 delivered by Respimat1 were closest and slightly superior to that of the 100/40 mg dose via MDI, respectively (fig. 3). Evaluation of the data for the secondary endpoints in this study produced similar results, with a log-linear dose-response relationship across the range of F/I doses administered by Respimat1, for the adjusted mean changes in peak FEV1 from predose for all eight treatments. Again, no clear dose relationship was evident between the two F/I doses given via MDI. The median time to onset of the therapeutic response with each active treatment ranged from min. Moreover, the median duration of the response exceeded the 6 h observation period for all treatments except for the 12.5/5 mg dose delivered by Respimat1 and the 100/40 mg dose via MDI. The median time taken to reach peak FEV1 was min for all active treatments. The efficacy results for the primary endpoint based on the per-protocol data were confirmed in corresponding analyses for the intent-to-treat patients (n~50, comprising the 47 per-protocol patients and three patients with missing data or protocol violations). Pharmacokinetics p= p= p= p= p= % confidence intervals L Fig. 3. Therapeutic equivalence comparisons for average forced expiratory volume in one second (AUC 0 6 h ): 90% confidence intervals and p-values for equivalence tests between fenoterol/ ipratropium (F/I) via Respimat1 and 100/40 mg F/I via metered dose inhaler. #: adjusted mean differences. The plasma concentration and urinary excretion of F are summarised in tables 2, 3 and 4. Administration by Respimat1 produced higher plasma values when compared with the same doses delivered by MDI. Excretion of F for equivalent doses also looked higher for Respimat1 100 mg and 50 mg, indicating a trend towards higher doses. Since the plasma concentration of I could not be detected by the radioreceptor assay, only the urinary excretion data are shown (tables 5 and 6). Following delivery of single doses of 20 or 40 mgofi the amounts of drug excretion were significantly higher for Respimat1 than the MDI. Overall, the pharmacokinetic studies indicated that the systemic exposure to

5 FENOTEROL/IPRATROPIUM DELIVERY BY RESPIMAT1 229 Table 2. Variability of plasma area under curve (AUC) and cumulative urinary excretion of fenoterol Dose mg Delivery device pg. ml -1. CI ng Patients Plasma AUC Urinary excretion n # h -1 95% 95% CI 12.5 Respimat Respimat Respimat Respimat Respimat MDI MDI Data are presented as adjusted geometric means, 95% confidence intervals (CI). # : pharmacokinetics evaluated statistically. Table 3. Comparison of adjusted geometric means of area under curve (AUC) data by pairwise t-test Doses mg Devices Adjusted geometric means of AUC p-value 12.5/25 Respimat1/Respimat1 11.0/ /50 Respimat1/Respimat1 55.1/ /100 Respimat1/Respimat1 69.6/ /200 Respimat1/Respimat / /100 Respimat1/Respimat1 55.1/ /200 Respimat1/Respimat1 69.6/ /50 Respimat/MDI 11.0/ /100 Respimat/MDI 55.1/ /50 Respimat/MDI 69.6/ /100 Respimat/MDI 125.5/ Table 4. Comparison of adjusted geometric means of urinary excretion data by pairwise t-test Active ingredient Doses mg Devices Adjusted geometric means of urinary excretion p-value Fenoterol 50/50 Respimat1/MDI 555.7/ /100 Respimat1/MDI 984.5/ F and I were proportional to the dose of drug inhaled. Furthermore, there was a two-fold greater systemic availability of both drugs following inhalation via Respimat1 compared with the MDI. Safety In general, the treatments were safe and well tolerated. A total of 33 adverse events were reported during the study (table 7). No adverse events were reported with the lowest F/I dose of 12.5/5 mg. The numbers of patients with adverse events were similar following placebo (5/30 patients exposed) and the highest F/I dose via Respimat1 (5/30). The incidence of adverse events in the other treatment groups was low and without a clear dose-relationship. No adverse event was seen in more than two patients on any treatment day. Paradoxical bronchoconstriction was experienced by 2 of the 29 patients in the placebo group. These findings were, however, nonsymptomatic and were not recorded as adverse events. There was one serious event: an asthma exacerbation due to a respiratory tract infection which required overnight hospitalization and was judged to be unrelated to the test drug. The patient recovered and was able to complete the trial as planned. Two adverse events led to withdrawal. One patient withdrew from the study 1 2 weeks after test day 2 due to symptoms of cold, fever and bronchitis. Another patient withdrew from the study on the first test day following drug inhalation (200/80 mg F/I by Respimat1) after experiencing a syncope during blood sampling, attributed to neurovegetative dystonia. Comparisons between physical examinations, ECG Table 5. Adjusted geometric means, 95% confidence intervals (CI) Dose mg Delivery device Urinary excretion ng geomean 95% CI 20 Respimat MDI Respimat MDI

6 230 J. GOLDBERG ET AL. Table 6. Comparison of adjusted geometric means of urinary excretion data of ipratropium bromide by pairwise t-test Active ingredient Doses mg Devices Adjusted geometric means of urinary excr. p-value Ipratropium 20/20 Respimat1/MDI 533.1/ /40 Respimat1/MDI / Table 7. Total drug exposure and adverse events with each treatment Patients with at least one adverse event/patients exposed Treament F/I dose in mg Delivery device n % Adverse events (n) Placebo Respimat1 5/30 17% Headache (1), hypotension (1), F/I 12.5/5 Respimat1 0/30 0% cough (1), dyspnoea (2) F/I 25/10 Respimat1 2/33 6% Headache (1), nervousness (1), F/I 50/20 Respimat1 1/33 3% pharyngitis (1) hypertension (1) F/I 100/40 Respimat1 3/29 10% Nervousness (1), tremor (1), cough (1) F/I 200/80 Respimat1 5/30 17% Malaise (1), nervousness (2), tremor (2), upper respiratory tract infection(1) F/I 50/20 MDI 2/31 6% Headache (1), dypsnoea (1) F/I 100/40 MDI 3/32 9% Headache (1), nervousness (1), agitation (1) Washout 6/53 11% Fever (1), headache (1), nervousness (1), viral infection (4), asthma (1), pharyngitis (1), upper respiratory tract infection (1) recordings and laboratory screening tests, carried out prior to admission to the study and after completion, showed no differences. The number of patients with clinically significant changes in vital signs was low and balanced across the eight treatments (table 8). Discussion In this study, all F/I treatments produced clinically relevant improvements in bronchodilatory efficacy, including a combined F/I dose of 12.5/5 mg via Respimat1. In addition, a log-linear dose-response relationship was obtained across the range of F/I doses administered by Respimat1 for the primary endpoint, AUC 0 6 h. No dose-response relationship was observed for the F/I doses given by MDI. Comparison of AUC 0 6 h values failed to demonstrate therapeutic equivalence between the MDI and any of the F/I doses administered by Respimat1, due to a substantially higher than expected variability. This may be related to the wide range of responses observed, which is associated with the relatively high level of airway reversibility in this group of patients. Although therapeutic equivalence could not be demonstrated statistically, the responses to F/I doses of 12.5/5 and 25/ 10 mg administered via Respimat1 were closest or slightly superior to that for the F/I dose of 100/40 mg delivered via MDI. In agreement with results for the AUC 0 6 h increase, Table 8. Number of patients with clinically significant changes in vital signs for each treatment Treatment F/I dose in mg Delivery device Systolic blood pressure Diastolic blood pressure Cardiac frequency E F E F E F Placebo Respimat F/I 12.5/5 Respimat F/I 25/10 Respimat F/I 50/20 Respimat F/I 100/40 Respimat F/I 200/80 Respimat F/I 50/20 MDI F/I 100/40 MDI Arrows represent a clinically significant increase (F) or decrease (E) in blood pressure or cardiac frequency.

7 FENOTEROL/IPRATROPIUM DELIVERY BY RESPIMAT1 231 the dose-response curves of peak increase of FEV1,also indicated log-linearity across the range of F/I doses administered by Respimat1 and no clear dose-response relationship between MDI doses. All F/I treatments showed a rapid onset of effect (medians ranged from min), and extended duration of bronchodilation (over 6 h), with a median time to peak effect ranging from min. The pharmacodynamics in the study agree well with those of other studies of F/I administered via MDI. For example, RAMMELOO et al. [29] showed an onset of response within 10 min, peak effect after 1 h, and duration of response over 6 h. Pharmacokinetic analyses demonstrated systemic availabilities of F and I following administration via Respimat1, based on adjusted mean AUC values in plasma and cumulative 0 6 h excretion in urine, were at least double those obtained following administration by MDI. However, as others have emphasized, pharmacokinetic results cannot be directly translated into pharmacodynamic responses [30]. The absence of close correlation is supported by the observation of high intersubject variability in spirometric data. All treatments of F/I were well tolerated whether administered by Respimat1 or by the conventional MDI. There was no indication of clinically relevant changes in cardiac frequency or systolic and diastolic blood pressure, with any of the eight study treatments. In addition, there was no worsening in ECG or physical examination compared to baseline, in any of the patients. Overall, the incidence of adverse events throughout this study was generally low. There was a slightly higher incidence of typical systemic betaadrenergic reactions of nervousness and tremor in the highest Respimat1 dosage group, reflecting the higher systemic drug exposure. The superior device performance of Respimat1 when compared to a conventional MDI has also been reported by MAESEN et al. [31]. In a dose-ranging study, doses of F given via Respimat1 or MDI were compared in 61 asthmatic patients. F doses of 12.5 and 25 mg administeredbyrespimat1 were therapeutically equivalent to a 100 mg dose delivered via MDI. In conclusion, the results of the present study show that fenoterol hydrobromide and ipratropium bromide delivery by Respimat1 is as safe and as efficacious in patients with stable asthma, compared with a pressurised metered dose inhaler, at considerably lower doses. Further studies are required to confirm the efficacy and safety of fenoterol hydrobromide and ipratropium bromide delivery by Respimat1 in the long-term treatment of patients with asthma and chronic obstructive pulmonary diseases. References 1. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987; 136: Beveridge RC, Grunfeld AF, Hodder RV, Verbeek PR. Guidelines for the emergency management of asthma in adults. CAEP/CTS Asthma Advisory Committee. Canadian Association of Emergency Physicians and the Canadian Thoracic Society. CMAJ 1996; 155: Sheffer AL, Taggart VS. The National Asthma Education Program. Expert panel report guidelines for the diagnosis and management of asthma. National Heart, Lung and Blood Institute. Med Care 1993; 31: MS20 MS Guidelines on the management of asthma. Statement by the British Thoracic Society, the British Paediatric Association, the Research Unit of the Royal College of Physicians of London, the King9s Fund Centre, the National Asthma Campaign, the Royal College of General Practitioners, the General Practitioners in Asthma Group, the British Association of Accident and Emergency Medicine, and the British Paediatric Respiratory Group. Thorax 1993; 48: S21 S Fireman P. B2 agonists and their safety in the treatment of asthma. Allergy Proc 1995; 16: Nicklas RA. National and international guidelines for the diagnosis and treatment of asthma. Curr Opin Pulm Med 1997; 3: British Thoracic Society, National Asthma Campaign, Royal College of Physicians of London. The British guidelines on asthma management: 1995 review and position statement. Thorax 1997; 52: S Traunecker W, Muacevic G. Pharmacological effects of a combination of fenoterol hydrobromide and ipratropium bromide. Respiration 1986; 50: Molkenboer JFWM, Cornelissen PJG. A double-blind randomised cross-over study assessing the efficacy of Berodual in comparison to its components ipratropium bromide and fenoterol in chronic bronchitis. Postgrad Med J 1987; 64: 19a 20a. 10. Chakravarti A, Pratley M, Barcharb J, et al. Ipratropium-fenoterol interaction study in asthmatic adults. Postgrad Med J 1987; 63: 5a. 11. Baculard A. Role of Bronchodual in the long-term treatment of asthma in children. Arch Pediatr 1995; 2: 149S 153S. 12. Pavia D. Efficacy and safety of inhalation therapy in chronic obstructive pulmonary disease and asthma. Respirology 1997; 2: 5s 20s. 13. Pavia D, McLeod L. The environmental impact of inhaled aerosols. Eur Respir Rev 1994; 4: Partridge M, Woodcock A. Metered dose inhalers free of chlorofluorocarbons. BMJ 1995; 310: Wetterlin K. Turbuhaler: A new powder inhaler for administration of drugs to the airways. Pharm Res 1988; 5: Zierenberg B, Eicher J, Dunne S, Freund B. Boehringer Ingelheirn Nebulizer BINEB1 a new approach to inhalation therapy. Respir Drug Deliv V 1996; Steed KP, Towse LJ, Freund B, Newman SP. Lung and oropharyngeal depositions of fenoterol hydrobromide delivered from the prototype III handheld multidose Respimat nebuliser. Eur J Pharm Sci 1997; 5: Newman SP, Steed KP, Reader SJ, Hooper G, Zierenberg B. Efficient delivery to the lungs of flunisolide aerosol from a new portable hand-held multidose nebuliser. J Pharm Sci 1996; 85: Steed KP, Freund B, Towse L, Newman SP. High lung deposition of fenoterol from BINEB1, a novel multiple dose nebuliser device. Eur Respir J 1995; 8: 204s.

8 232 J. GOLDBERG ET AL. 20. Steed KP, Zierenberg B, Reader S, Newman SP. Lung deposition of flunisolide from BINEB1, a novel multiple dose nebuliser, is twice that from a pressurised metered dose inhaler. Eur Respir J 1995; 8: 122s. 21. Newman SP, Steed KP, Towse L, Zierenberg B. The BINEB1 (final prototype): a novel hand-held multidose nebuliser evaluated by gamma scintigraphy. Eur Respir J 1996; 9: 441s 442s. 22. Newman SP, Brown J, Steed KP, Reader SJ, Kladders H. Lung deposition of fenoterol from Respimat1, a novel inhaler device for pulmonary drug delivery. J Aerosol Med 1997; 10: Newman SP, Brown J, Steed KP, Reader SJ, Kladders H. Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicines: comparison of Respimat1 with conventional metered-dose inhalers with and without spacer devices. Chest 1998; 113: Maesen FPV, Smeets JJ, Smeets P, Wald FDM, Cornelissen PJG. A pilot study to compare the efficacy and safety of fenoterol administered from an MDI with a metered dose solution from a novel device (BINEB1). Eur Respir J 1995; 8: 258s. 25. Maesen FPV, Smeets JJ, Smeets P, Wald FDM, Comelissen PJG. A pilot study to compare the efficacy and safety of ipratropium bromide administered from an MDI with a metered dose solution from a novel device (BINEB1). Eur Respir J 1995; 8: 426s. 26. American Thoracic Society. Medical Section of the American Lung Association. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987; 136: Standardization of spirometry-1987 update. Statement of the American Thoracic Society. Am Rev Respir Dis 1987; 136: Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Report of the Working Party on Standardization of Lung Function Tests. European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J 1993; 16: Rammeloo RHU, Luursema PB, Sips AP, Beumer HM, Wald FDM, Cornelissen PJG. Therapeutic equivalence of a fenoterol/ipratropiurn bromide combination (Berodual) inhaled as a dry powder and by metered dose inhaler in chronic obstructive airway disease. Respiration 1992; 59: Chrystyn H. Standards for bioequivalence of inhaled products. Clin Pharmacokinet 1994; 26: Maesen FPV, van Noord JA, Smeets JJ, Greefhorst APM, Dewberry H, Cornelissen PJG. Dose-range finding study comparing a new soft mist inhaler with a conventional metered dose inhaler (MDI) to deliver fenoterol in patients with asthma. EurRespirJ 1997; 10: 128s.